A comprehensive analysis of the molecular landscape of HER3 expression in adenocarcinoma of the lung
Recommended Citation
Alhushki SK, Al-Bzour AN, Al-Bzour NN, Abushukair HM, Abu Rous F. A comprehensive analysis of the molecular landscape of HER3 expression in adenocarcinoma of the lung. ESMO Open 2024; 9.
Document Type
Conference Proceeding
Publication Date
3-1-2024
Publication Title
ESMO Open
Abstract
Background: HER3, a member of the epidermal growth factor family, is aberrantly expressed in lung cancer. It is a promising target for treatment with many antibody-drug conjugates (ADCs) developed, including Patritumab deruxtecan. In our study we aim to evaluate the difference between HER3 high and low groups based on a comprehensive multiomics analyses. Methods: We utilized The Cancer Genomic Atlas lung adenocarcinoma (LUAD) project data. Clinical, histopathological, genomic, and proteomic data for 599 LUAD patients was retrieved through the cBioPortal database. Patients with the highest and lowest 25% HER3 mRNA expression were grouped into the high- and low-HER3 groups, respectively. Differential gene expression analysis was conducted using the DESeq2 R package and enrichment analysis for upregulated genes was done using the gene ontology (GO) and KEGG pathways libraries. Results: LUAD patients with mRNA expression data (n=510) were grouped into high-HER3 (Z-score: 3.11-7.25, n=128) and low-HER3 (Z-score: -20.47-0.23, n=127). High-HER3 patients had a trend for higher age (68.0 vs. 63.0, p=0.052) compared to the low-HER3 group. Overall survival and progression-free survival were not significantly different between the two groups. Mutational analysis showed that KRAS, STK11, and CDKN2B were more commonly mutated in the high-HER3 group, whereas mutations in TP53, PCDHB8, CDK12, and CD274 (PD-L1) were more common in the low-HER3 group. In terms of mRNA expression, immune checkpoint genes such as PDCD1, CD274, CTLA4, and LAG3 were more expressed in low-HER3 group. Moreover, immune infiltration analysis using CIBERSORT algorithm showed significantly higher levels of CD4+ activated memory T cells and M1 macrophages in the low-HER3 group. The enriched pathways in the low-HER3 group were related to ‘CXCR chemokine receptor binding’, ‘TNF signaling’, and ‘IL-17 signaling’ pathways. Conclusions: Low-HER3 patients might experience improved responses to immunotherapy due to higher expression of immune checkpoint genes and higher infiltration of immune cells. High-HER3 patients had more KRAS mutations which could be a target for combination therapy in addition to HER3 ADCs. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Volume
9
